Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia

Deciphering the evolution of cancer cells under therapeutic pressure is a crucial step to understand the mechanisms that lead to treatment resistance. To this end, we analyzed whole-exome sequencing data of eight chronic lymphocytic leukemia (CLL) patients that developed resistance upon BCL2-inhibition by venetoclax. Here, we report recurrent mutations in BTG1 (2 patients) and homozygous deletions affecting CDKN2A/B (3 patients) that developed during treatment, as well as a mutation in BRAF and a high-level focal amplification of CD274 ( PD-L1 ) that might pinpoint molecular aberrations offering structures for further therapeutic interventions. BCL2-inhibitor venetoclax is used to treat relapsed/refractory chronic lymphocytic leukemia (CLL). Here, the authors show the clonal dynamics towards venetoclax resistance by performing whole-exome sequencing of 8 CLL patients undergoing venetoclax treatment.